Heme oxygenase (HO) produces carbon monoxide (CO) during the breakdown of heme molecules. This enzymatic activity exists mainly in two forms: HO-1 and HO-2. HO-1 is known as stress-inducible heat shock protein 32, which is upregulated by a variety of stressors—including cytokines, hypoxia, and reactive oxygen species—that are generated under certain disease conditions, including ischemia-reperfusion (1). Synthesized CO diffuses out of cells, enters the blood to form carboxyhemoglobin (COHb) and is transported to the lungs, where it is excreted in the ambient air (2). Thus, exhaled CO levels could reflect the induction of HO-1.
Exhaled CO levels have been reported to increase in inflammatory airway disease (3,4), severe sepsis (5), and in critically ill patients (6). Exhaled CO and arterial COHb increase after surgery under both general and spinal anesthesia, which may be due to oxidative stress caused by anesthesia or surgery (7). Endogenous CO production, calculated by exhaled CO levels, correlates weakly with the severity of acute illness and might reflect the severity of acute organ dysfunction (8). Thus, measurement of exhaled CO during mechanical ventilation could be a new method for evaluating the severity of inflammatory airway disease, acute organ dysfunction, or stress by surgery and anesthesia. To use this measurement during mechanical ventilation, it is important to clarify the effects of factors that interfere with exhaled CO levels.
High fractions of inspired oxygen (Fio2) and mechanical ventilation are often used in critically ill patients or during general anesthesia. High Fio2 is generally used to treat patients with CO poisoning, as it increases elimination of CO and increases exhaled CO. It is important to understand the effects of the Fio2 on CO elimination when monitoring exhaled CO, apart from the setting of CO poisoning, in mechanically ventilated patients. To our knowledge, very little has been published regarding the effects of changes of Fio2 on exhaled CO levels in mechanically ventilated patients. The one investigation we were able to find demonstrates that pulmonary elimination of CO increases markedly, but transiently, with inspiration of Fio2 1.0 (9). To determine the precise effects of changes of Fio2 on exhaled CO, we initially investigated the effects of sequential changes of Fio2 on exhaled CO levels in mechanically ventilated patients during general anesthesia. Second, to determine the time course of the changes of exhaled CO levels by Fio2, we investigated the effects of long-term inhalation of Fio2 0.75 and 0.35 on exhaled CO levels and arterial COHb concentrations.
This study was approved by the Kitano Hospital ethics committee, and written informed consent was obtained from all patients. Thirty adult patients (18 yr or older), ASA PS 1–2, with no history of smoking, who were scheduled to undergo elective surgery were enrolled in this study. In Group 1 (n = 6), the effects of sequential changes of Fio2 on exhaled CO levels were investigated. In Group 2 (n = 12), the effects of long-term inhalation of Fio2 0.75 (n = 6) or 0.35 (n = 6) on exhaled CO levels were investigated. In Group 3 (n = 12), the effects of long-term inhalation of Fio2 0.75 (n = 6) or 0.35 (n = 6) on arterial COHb concentrations were investigated. After induction of anesthesia with thiopental and vecuronium, all patients were tracheally intubated. Anesthesia was maintained with sevoflurane (1%–2.5%) and intermittent administration of fentanyl and vecuronium. All patients were ventilated with a non-rebreathing ventilator (Servo 900C™, Siemens, Munich, Germany) at a fixed tidal volume (body weight kg × 10 mL) and respiration rate (10/min). Inspired gas concentrations were generated from liquid oxygen and liquid nitrogen. In Groups 1 and 2, exhaled CO levels were measured in gas sampled continuously (200 mL/min) from the expired limb of the respiration circuit by a Carbolyzer (mba2000, Taiyo, Osaka, Japan). The Carbolyzer measures CO levels continuously (every second) with a resolution of 0.1 ppm at a range of 0–50 ppm, using controlled potential electrolysis (10). Two-point calibration of the Carbolyzer was performed using a standardized gas before each measurement. The CO level in the inspired air was confirmed to be zero before measurement in every patient. In Group 3, the radial artery was catheterized for arterial blood pressure monitoring and intermittent sampling of arterial blood. In Group 1, after at least 1 h at Fio2 0.35, the Fio2 was increased to 0.55, 0.75 and 1.0 every 20 min, and decreased thereafter to 0.75, 0.55 and 0.35 every 20 min. The maximum changes of exhaled CO at every Fio2 were used for analysis. In the investigation of Fio2 0.75 in Groups 2 and 3, after at least 1 h at Fio2 0.35, we increased the Fio2 to 0.75. The 1 min average of exhaled CO levels just before the increase of Fio2 (basal level), the peak level, and CO levels at 30 min and every hour after the increase in Fio2 were used for analysis. Arterial blood samples were obtained just before the increase of Fio2 (basal level), and every hour after the increase of Fio2. In the investigation of Fio2 0.35 in Groups 2 and 3, the Fio2 was maintained at 0.35. Exhaled CO levels and arterial COHb concentrations were determined every hour after induction of anesthesia for subsequent analysis. The COHb concentrations were measured with a blood gas analyzer (ABL735, Radiometer, Copenhagen, Denmark).
All values are expressed as the mean ± sd. Exhaled CO and COHb data were first compared within each group using one-way analysis of variance with repeated measurements. When significant, post hoc comparison was performed with Student-Newman-Keuls test (Statistica Ver6, StatSoft JAPAN, Tokyo, Japan).
The average duration for all of the surgeries was 451 ± 321 min. The mean blood loss was 717 ± 798 g. In one case in Group 2 and three cases in Group 3, blood transfusion was performed after completion of the exhaled CO concentration or arterial COHb measurements. Oxygen saturation was stable and no significant morbid events, such as pulmonary edema, occurred during the operations.
Effects of Changes of Fio2 on Exhaled CO Levels
A representative example of the effects of changes of Fio2 on exhaled CO levels indicates the changes that were observed during each 20 min observation period (Fig. 1). After the increase of Fio2, exhaled CO levels increased rapidly and then decreased gradually over 20 min. After the decrease of Fio2, exhaled CO levels decreased rapidly and reached a plateau. Table 1 presents the maximum changes of exhaled CO levels at each Fio2 (n = 6). Exhaled CO levels increased significantly at Fio2 0.55 (5.20 ppm), 0.75 (6.70 ppm) and 1.0 (7.57 ppm) compared to the basal level (3.35 ppm). After the decrease of Fio2 from 1.0, exhaled CO levels remained significantly higher at Fio2 0.75 (4.97 ppm), but returned to the basal level at Fio2 0.55 (3.42 ppm). When the Fio2 was decreased to 0.35, exhaled CO levels became significantly lower than the basal level (2.20 vs 3.35 ppm).
Effects of Long-term Inhalation of Fio2 0.75 and 0.35 on Exhaled CO Levels
A representative example of the effects of long-term inhalation of Fio2 0.75 on exhaled CO levels demonstrates the rapid increase in exhaled CO after Fio2 was increased followed by a gradual decrease to a stable plateau after 2 h (Fig. 2). Peak exhaled CO measurements over time for all patients followed a similar pattern (Table 2). Exhaled CO levels did not exhibit significant change during long-term inhalation of Fio2 0.35 (Table 2).
Effects of Long-term Inhalation of Fio2 0.75 and 0.35 on Arterial COHb Concentrations
Arterial COHb was significantly lower than basal levels after the change in Fio2 to 0.75 (Table 3). In contrast, arterial COHb levels did not exhibit any significant change during long-term inhalation of Fio2 0.35 (Table 3).
In this study, we clearly demonstrated that exhaled CO levels change rapidly in response to small changes of Fio2 (0.2–0.25) in mechanically ventilated patients during general anesthesia. We have also shown that Fio2 0.75 increased exhaled CO levels, accelerated the elimination of CO from the body, decreased the blood COHb concentration, and finally, decreased the levels of exhaled CO to basal levels; but this change was not observed at Fio2 0.35.
It has been reported that CO is produced by the interaction of volatile anesthetics, including sevoflurane, and carbon dioxide absorbents (11,12). We eliminated the influence of CO production through this interaction in our study, as we used a non-rebreathing ventilator and did not use any carbon dioxide absorbents.
To observe the effects of a small change of Fio2, we performed a stepwise increase and decrease in each patient. The exhaled CO level at each step was likely influenced by the previous Fio2. Quantitative changes in the CO observed at each Fio2 could be different if the Fio2 sequence was different.
The principal physiological variables that determine blood concentrations of COHb, and therefore exhaled CO concentrations, are 1) rate of CO production, 2) alveolar ventilation, 3) diffusing capacity of the lung, 4) mean oxygen tension in the pulmonary capillaries, and 5) concentration of CO in the inspired air (2). In this study, we measured exhaled CO levels in mechanically ventilated patients during general anesthesia. Patients' lungs were ventilated with a fixed tidal volume and respiration rate, and thus, alveolar ventilation was kept constant. No blood transfusion was performed during the measurement. There was some degree of hemodynamic fluctuation in response to changing anesthetic depth and the degree of surgical stimulation, which could change pulmonary blood flow during measurements. However, these effects on exhaled CO levels might be smaller than the effects of change of Fio2, and could be cancelled out in statistical analysis with repeated measurements. Oxygen tension in the arterial blood was stable after the changes in Fio2, and no obvious events such as pulmonary edema occurred, suggesting that the diffusing capacity of the lung was constant. Inspired air was generated from liquid oxygen and liquid nitrogen, and CO was not detected from the inspired limb of the respiration circuit. Mean oxygen tension in the pulmonary capillaries and blood COHb concentrations are, thus, major determinants of the observed changes of exhaled CO levels. The initial changes of exhaled CO levels may be due to the change of mean oxygen tension in the pulmonary capillaries. CO and oxygen bind to the same site on hemoglobin and therefore compete against each other. The higher Fio2 induces an increase in the mean oxygen tension in pulmonary capillaries, to increase the affinity of hemoglobin to oxygen, resulting in increased elimination of CO from the blood through expiration. The lower Fio2 induces a lower mean oxygen tension in the pulmonary capillaries, to decrease the affinity of hemoglobin to oxygen, resulting in less elimination of CO from the blood through expiration. We demonstrated that the decrease of exhaled CO at least 1 h after the increase of Fio2 may be due to the decrease of COHb concentration, as a result of the elimination of CO from the body by increased elimination of CO from the lung.
Zegdi et al. (9) demonstrated that pulmonary elimination of CO was markedly, but transiently, dependent on Fio2, and suggested that pulmonary elimination of CO returned to a baseline value after several hours of high Fio2. We have shown that the return of exhaled CO levels to baseline after several hours of high Fio2 reflects the decrease of blood COHb concentrations. In support of this hypothesis, when the Fio2 was returned to the basal level after inhalation of high Fio2, exhaled CO levels were significantly lower than the basal level (Table 1).
This study demonstrated that we should address the effects of the concentration of inspired oxygen and its time course on exhaled CO levels in mechanically ventilated patients. It is possible to misinterpret high levels of exhaled CO induced by inspiration of high Fio2 as a reflection of the severity of inflammatory airway disease, acute organ dysfunction, or stress from surgery and anesthesia. It is standard procedure to deliver high concentrations of oxygen to such patients. However, other factors that might influence exhaled CO, such as blood transfusion, should be investigated in future studies.
In conclusion, we have clearly demonstrated that exhaled CO changes rapidly in response to small changes of Fio2, and that endogenous CO is eliminated from the body after long-term inhalation of high Fio2. Normal Fio2 (0.35) during mechanical ventilation does not cause such an obvious change after long-term inhalation. When exhaled CO levels are determined in mechanically ventilated patients, the consequences of changes of Fio2 and its duration must be considered when interpreting these measurements.
1. Suematsu M. COHb: a stress-induced marker reflecting surgical insults. J Gastroenterol Hepatol 2002;17:519–20
2. Coburn RF, Forster RE, Kane PB. Considerations of the physiological variables that determine the blood carboxyhemoglobin concentration in man. J Clin Invest 1965;44:1899–910
3. Yamaya M, Sekizawa K, Ishizuka S, Monma M, Mizuta K, Sasaki H. Increased carbon monoxide in exhaled air of subjects with upper respiratory tract infections. Am J Respir Crit Care Med 1998;158:311–4
4. Zayasu K, Sekizawa K, Okinaga S, Yamaya M, Ohrui T, Sasaki H. Increased carbon monoxide in exhaled air of asthmatic patients. Am J Respir Crit Care Med 1997;156:1140–3
5. Zegdi R, Perrin D, Burdin M, Boiteau R, Tenaillon A. Increased endogenous carbon monoxide production in severe sepsis. Intensive Care Med 2002;28:793–6
6. Scharte M, Bone HG, Van Aken H, Meyer J. Increased carbon monoxide in exhaled air of critically ill patients. Biochem Biophys Res Commun 2000;267:423–6
7. Hayashi M, Takahashi T, Morimatsu H, Fujii H, Taga N, Mizobuchi S, Matsumi M, Katayama H, Yokoyama M, Taniguchi M, Morita K. Increased carbon monoxide concentration in exhaled air after surgery and anesthesia. Anesth Analg 2004;99:444–8
8. Scharte M, von Ostrowski TA, Daudel F, Freise H, Van Aken H, Bone HG. Endogenous carbon monoxide production correlates weakly with severity of acute illness. Eur J Anaesthesiol 2006;23:117–22
9. Zegdi R, Caid R, Van De LA, Perrin D, Burdin M, Boiteau R, Tenaillon A. Exhaled carbon monoxide in mechanically ventilated critically ill patients: influence of inspired oxygen fraction. Intensive Care Med 2000;26:1228–31
10. Sawano M, Mato T, Tsutsumi H. Bedside red cell volumetry by low-dose carboxyhaemoglobin dilution using expiratory gas analysis. Br J Anaesth 2006;96:186–94
11. Keijzer C, Perez RS, De Lange JJ. Carbon monoxide production from five volatile anesthetics in dry sodalime in a patient model: halothane and sevoflurane do produce carbon monoxide; temperature is a poor predictor of carbon monoxide production. BMC Anesthesiol 2005;5:6
© 2007 International Anesthesia Research Society
12. Wissing H, Kuhn I, Warnken U, Dudziak R. Carbon monoxide production from desflurane, enflurane, halothane, isoflurane, and sevoflurane with dry soda lime. Anesthesiology 2001;95:1205–12